- Pancreatic ductal adenocarcinoma is the most common type of pancreatic cancer, and it can be challenging to treat.
- One struggle is tumor resistance to a group of medications called RAS(ON) inhibitors.
- A study involving mice found that a combination of the RAS(ON) inhibitor daraxonrasib with two other medications effectively helped to treat pancreatic ductal adenocarcinoma while successfully avoiding tumor resistance.
According to the
Over 90% of pancreatic cancer cases are pancreatic ductal adenocarcinoma. Thus, finding ways to treat pancreatic cancer is an area of critical research.
Fortunately, treatment options may be advancing in this area. A recent study published in PNAS that used mouse models confirmed the effectiveness of a combination therapy for pancreatic ductal adenocarcinoma.
Future research can move toward seeing if the therapy would be effective in people.
The researchers point out that a recent problem with treating pancreatic cancer is tumor resistance to RAS(ON) inhibitors. These drugs target certain proteins produced by the
In pancreatic ductal adenocarcinoma, mutations often occur in this gene.
Researchers worked with mouse pancreatic cell lines, mouse cancer cells that were engrafted into mice, tumors from humans, and tumors from humans that were implanted in mice.
They monitored tumor size, and were also able to analyze the mice’s blood following euthanization.
To start off this study, researchers demonstrated that targeting three key components of the KRAS signaling pathway via genetic ablation can help pancreatic tumors to regress.
They demonstrated that a component of the signaling pathway called signal transducer and activator of transcription 3 (STAT3) is particularly critical to block.
The authors assert and explain with their work that when the two other factors are blocked via genetic ablation, activation of this third component leads to tumor resistance.
They used mice to show that eliminating these three components led to long-term elimination of pancreatic tumors. The data also indicated that tumor resistance did not occur.
Next, researchers tested a combination of three medications: daraxonrasib, afatinib, and SD36. They examined how they affected pancreatic cancer.
This combination effectively killed pancreatic ductal adenocarcinoma cells. However, the medications all have to be used at the same time, because the tumors that became resistant to daraxonrasib did not respond to adding the other two medications afterwards.
In further research in mice, the trio of meds effectively regressed tumors, and the effects were long-lasting. The treatment was also well-tolerated by the mice. The authors note that this suggests the medication trio was effective in preventing tumor resistance.
Further testing in vitro, in mice with genetically engineered mouse tumors, and in mice with tumors that were implanted from people produced similar results.
For example, among the mice with the genetically engineered mouse tumors, there was a complete regression for half of the mice who received the trio of medications.
Further research also suggested that using other KRAS inhibitors could also be effective when combined with the two other medications.
Study author Carmen Guerra, PhD, and Staff Scientist at the Spanish National Cancer Centre (CNIO) explained the research to Medical News Today, noting:
“We have developed a triple therapy that completely eliminates the tumors. This therapeutic benefit lasts on time and we have not observed tumor relapses. This has been done using several mouse models. This strategy opens the door to better therapeutic strategies (personalized and precision medicine). But we still have a long way to go before we learn if this therapy can be of therapeutic benefit in the clinic.”
This research is a critical preliminary step, but more research is needed to see how effective this combination therapy will be in people. Since the research on the combination therapy was conducted in mice, it is unclear how well it will work with people.
Researchers also note that the drug afatinib currently does not have approval to be used as a treatment for pancreatic ductal adenocarcinoma, which is another struggle when it comes to translating this into clinical practice.
Mice also received a much higher dose of daraxonrasib than what has been used in similar research, so dosing considerations may also be important.
There are also struggles related to finding other medications that would be most effective in clinical practice. For example, there were still differences between the genetic ablation technique and the use of medication. Dosing considerations will also be important.
Finally, it is important to note that this research may not apply to other pancreatic tumors or those not caused by certain mutations.
Nevertheless, this study offers hope in developing treatments for pancreatic cancer.
Anton Bilchik, MD, PhD, a surgical oncologist, chief of medicine, and Director of the Gastrointestinal and Hepatobiliary Program at Providence Saint John’s Cancer Institute in Santa Monica, CA, who was not involved in this research, shared his perspective on the findings.
“Pancreas cancer is one of the deadliest cancers,“ Bilchik emphasized. “Treatment options have been limited and most patients only present with symptoms once they have advanced incurable disease.“
“More recently, more targeted therapies against the KRAS gene have shown therapeutic promise. However,“ he cautioned, “the benefits are short-lived since pancreatic cancers rapidly develop resistance.“
“This research is extremely exciting and novel since it shows how this resistance can be overcome in a mouse model. The next steps which are clearly more complex are to evaluate the safety and efficacy in humans in clinical trials. If successful, this will be practice changing in the management and treatment of one of the deadliest cancers.”
– Anton Bilchik, MD, PhD
Guerra further noted that the research team who conducted this study is “working on developing and testing better drugs for these targets.“
“For this, we are currently collaborating with a small Biotec, Vega Oncotargets,“ the study author shared. “We are also testing this triple therapy in metastasis and in mouse models that carry different mutations, in order to find potential resistances to this therapy. In that case, we will study the mechanisms of resistances to be able to develop new therapeutic strategies.”
